髓样分化蛋白2（MD2）在血管紧张素II（AngII）诱导的炎症反应及心室重构中的作用和机制研究

Angiotensin II (AngII) has an important role in the biological process leading to cardiac remodeling. In addition to its physiological role in arterial blood pressure regulation, AngII directly induces myocardial remodeling through the inflammation. However, it remains an open question to precisely describe how inflammation is activated by AngII, resulting in the remodeling in heart.TLR4 and MD2 play important roles in LPS-induced inflammation. Although TLR4 has been demonstrated as an important regulator in cardiac remodeling, the direct mechanism remains to be elucidated. Our previous study found that a novel small molecule L6H21, which targets MD2 protein and inhibits LPS-induced inflammatory response, could inhibit AngII-induced inflammation and cardiac remodeling development in vivo. Thus, we hypothesize that, MD2 plays an important role in mediating AngII-induced inflammation and MD2 may be a new target for the treatment of cardiac remodeling. In this project, we plan to demonstrate the mechanisms of MD2 in AngII-induced inflammation and cardiac remodeling and prove the mechanisms that AngII binding directly with MD2 is required in activation of the TLR4/MD2 inflammatory signals in the molecular, cellular, and animal levels. These studies will demonstrate the effects and mechanisms of AngII-induced inflammation and provide a new therapeutic target for cardiac remodeling and heart failure treatment.

血管紧张素II（AngII）在心室重构中有着重要作用。除调节血压外，AngII还可以通过炎症直接介导心室重构，但该过程的机制尚不清楚。在内毒素诱导的炎症反应中，Toll样受体4（TLR4）和髓样分化蛋2（MD2）共同发挥着重要作用。虽研究表明TLR4参与了AngII诱导的炎症及心室重构，但其直接机制有待阐明。我们前期研究发现一个MD2小分子抑制剂L6H21可以抑制AngII诱导的炎症反应，并在体内显著缓解心脏炎症和心室重构。基于此，我们假设：1）MD2在AngII诱导的炎症反应中起重要的介导作用；2）MD2可以作为缓解心室重构的新靶点。本项目拟从分子、细胞和动物三个层面，深入阐明MD2介导AngII诱导的炎症反应和心室重构的分子机制，证实AngII通过直接结合MD2并引起MD2/TLR4炎症信号通路激活的促炎机制。项目将阐明AngII促炎机制并为缓解心室重构及减慢心力衰竭提供新的治疗靶点

本项目总目标在于明确MD2介导的炎症在高血压心衰的发生发展中的重要作用，证实MD2可以作为缓解高血压心衰的新靶点，阐明前期发现的以MD2为直接靶点的新化合物L6H21缓解高血压心衰的药理分子机制。 .我们前期的实验过程中发现L6H21是MD2蛋白的小分子抑制剂，且化合物L6H21能够缓解LPS诱导的脓毒血症和急性肺损伤的表型。本项目的实施阐明了MD2介导高血压心衰的药理机制，确证了MD2可以作为缓解高血压心衰的新靶点，为动高血压心衰的治疗提供了新的候选药物。本项目的实施完成了申请书中的项目目标。